Drug-Drug Interactions

Drug-drug interactions involves inhibition and/or induction of drug metabolizing enzymes. Inhibition of drug metabolizing enzymes is a major mechanism of drug-drug interactions. The majority of these enzymes are CYPs.

CYP Inhibition Studies

These studies are conducted with HLM or recombinant enzymes, FDA-accepted probe substrates, and control inhibitors. Both IC50 and Ki values can be determined, and the pre-incubation of the test article with microsomes and NADPH are used to assess time-dependent inhibition. Alternatively, we can use recombinant CYP450 enzymes with fluorogenic probe substrates in screening assays.

UGT Inhibition Studies

Recombinant UGT enzymes are used to assess the IC50 values of a test article with respect to the most common isoforms.

CYP Induction Studies

Enzyme induction following drug administration can lead to enhanced clearance of co-medications or itself, causing a drug-drug interaction, therapeutic failure, patient management, and potentially other safety issues. Cryopreserved human hepatocytes from one or more donors are used to assess the potential of a compound to induce the activity of a drug metabolizing CYP. In addition to directly studying enzyme activity, we are also able to determine CYP mRNA or protein expression induction using RT-PCR or Western Analysis, respectively (two FDA-accepted validation methods) upon request by the clients.